Process of preparing z-amino



' as follows:

Patented Aug. 25, 1953 stain PROCESS or PREPARING aAMmo- QUINOXALINE COMPOUNDS Karl Pfister III, Scotch Plains, and John Weijlard,

. J., assignors to Merck & (10., Inc.,

Rahway, N. .L, a corporation of New Jersey No Drawing. Application October 23,1948, Serial No. 56,256

14 Claims. (01. 260-250) This invention relates to an improved method generally applicable for the preparation of 2- aminoquinoxaline compounds which are important intermediates in the manufacture of the corresponding .sulfaquinoxalines. The sulfaquinoxalines are bacteriostatic agents especially useful in veterinary medicine. They are also of value as antimalarial agents.

Z-aminoquinoxaline, the precursor of sulfaquinoxaline, has been prepared previously by hydrolysis and decarboxylation of alloxazine, which is ordinarily prepared by reacting orthophenylenediamine with alloxan. The alloxan starting material, however, is costly and relatively non-available and the hydrolysis procedure ordinarily employed, whichutilizes concentrated We have now discovered, however, a new and improved process for preparing. 2 aminoquinoxaline which employs available and relatively inexpensive starting materials and which does not require the use of high pressures. We have further discovered that this novel process is gen erally applicable for preparing Z-aminoquinoxaline compounds containing substituents in the benzenoid nucleus and, in particular those 2- aminoquinoxalines which contain halo, alkyl or alkoxy substituents.

This process may be chemically represented 1 1 1 g NH, NHCHZON I NH: NH: I Ny 2 2 a,

wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl and alkOXy radicals.

The reactions indicated above are carried out as follows: a 1,2-diamino-benzene compound (1) is reacted with formaldehyde and hydrogen cyanitrile to produce an N (o-aminophenyD-glycine nide or with glycolonitrile, or with a haloacetonitrile compound (2); this compound is then treated, in methanolic solution, with a strong base, thereby cyclizing the nitrile to produce the corresponding Z-amino 3,4 dihydroquinoxaline compound (3) which is converted to the corresponding z-aminoquinoxaline compound (4) by treatmentwith an oxidizing agent.

The 1,2-diamino-benzene compounds, which can be used as starting materials in practicing the present invention are those compounds which can bechemically represented as follows:

B, V wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl and alkoxy radicals. This class of starting materials includes ortho-phenylenediamine, halogenated ortho phenylenediamines such as 3- chloro 1,2 diaminobenzene, 4-chloro 1,2 diaminobenzene, and the like, alkylated orthophenylenediamines, such as 3-methyl 1,2 diaminobenzene, i-methyl 1,2 diaminobenzene,

4.5- dimethyl 1,2 diaminobenzene, 4-ethyl- 1,2-diaminobenzene, i-isopropyl-1,2-diaminobenzene, and the like, and alkoxy substituted orthophenylenediamines, such as 4-methoxy-L2- diaminobenzene, 3-methoxy-1,2-diaminobenzene, 4,5-dimethoxy-1,2-diaminobenzene, 4-eth0xy-L2- diaminobenzene,3 propoxy 1,2 diaminobenzene, and thelike.

The conversion of the 1,2-diaminobenzene compound to the corresponding ,N-(o-aminophenyl) -glycine nitrile compound can be accomplished by reacting said 1,2-diaminobenzene compound with glycolonitrile. This reaction is conveniently carried out using equimolecular quantities of reactants, although an excess of diamine may be utilized if desired. An excess of glycolonitrile over the diamine, however, should be avoided since this results in the incyanomethyl-o-phenylenediamine. For example, when an excess. (about 10%) of glycolonitrile is employed, an increase in physical yield results but the product is of poor quallty and contains a high proportion of the dicyano derivative. It is therefore preferred to employ equimolecular proportionsof reactants;

The reaction is ordinarily conducted by heating the reactants in solution preferably using water or aqueous alcohol as the solvent. When the reaction is carried out in alcoholic media, however, the product obtained is ordinarily of poor quality; it is therefore preferred to conduct the reaction by heating the reactants using water as the only solvent. The reaction temperature is critical in that ,no reaction occurs below about C. and it has been found desirable to employ a reaction temperature of at least about C. Although temperatures up to 95 C. have given excellent yields of good quality material, it is ordinarily preferred to conduct the reaction at a temperature between 60 and C. The pH during the reaction is also critical and should be adjusted to between about 6.0 and 7.0. No reaction occurs at pH=-3; at pH values above about 7.0, the product is gummy. At a pH value within the range 6.0-6.2, the yield and quality of the product is satisfactory, but the condensation requires a temperature of at least about 90 C. It is therefore ordinarily preferred to employ a pH within the range of 6.5-7.0 under which conditions the reaction proceeds satisfactorily at the preferred temperature of 60-65 C. The optimum reaction time varies depending on the temperature and the pH; at Gil-65 C., the reaction is ordinarily allowed to proceed for approximately two hours; at 90-95 C. the reaction is about 80% completed in 8 minutes and is substantially complete in /2 hour; no appreciable change in yield results when the condensation time is increased from /2 hour to one hour at 90-95" C. When the reaction is carried out in water, the N-(o-aminophenyl)-glycine compound precipitates directly from the aqueous reaction mixture and is recovered by filtration.

Instead of glycolonitrile, a haloacetonitrile, such as chloroacetonitrile or bromoacetonitrile, can be reacted with the 1,2-diaminobenzene compound to produce the desired N-(o-aminophenyl) -glycin nitrile compound. This reaction is conveniently carried out by heating the diamine and the haloacetonitrile in the presence of a base, such as pyridine. It is ordinarily preferred to conduct the reaction by heating substantially equimolecular proportions of the reactants in solution in a lower aliphatic alcohol.

It is important to avoid using an excess of haloacetonitrile since this results in appreciable formation of unwanted N,N-dicyano-1,2-diaminobenzene by-products. The desired N-(o-aminophenyl)-glycine nitrile compound is conveniently separated from the reaction mixture by triturating said mixture with water (after evaporation of the alcohol when the reaction is carried out in this solvent) thereby precipitating the desired nitrile as a granular product.

The presently preferred process for accomplishing the conversion of the 1,2-diaminobenzene compound to the corresponding N-(o-aminophenyl) -glycine-nitrile compound is by reacting said diamino-compound with formaldehyde and hydrogen cyanide. As in the case of the reactions employing glycolonitrile or haloacetonitrile, it has been found best to employapproximately equimolecular proportions of reactants and, in particular, to avoid using an excess of formalde hyde and hydrogen cyanide, since this results in production of considerable amounts of the unwanted N,N-dicyano-1,2-diamino-benzene comv pound. The procedure can be carried out by first reacting the 1,2-diaminobenzene compound, such as ophenylenediamine, with formaldehyde in the presence of sodium bisulfite, and treating the reaction mixture, without purification, with a cyanide salt, such as an alkali cyanide. The reaction between the 1,2-diaminobenzene compound, formaldehyde and sodium bisulfite is conveniently conducted in aqueous solution at a tem perature below about 60 C. The resulting mixture is then reacted, without further treatment, with a cyanide salt, the reaction being carried out at a temperature of about -85" C. The N-(o-aminophenyl)-glycine nitrile compound thus produced is isolated directly from the reaction solution by cooling and crystallizing.

An improved modification of the above procedure involves reacting the 1,2-diaminobenzene compound with hydrogen cyanide and formaldehyde, said reaction being carried out in water or preferably water plus sufiicient methanol or other water-miscible lower aliphatic alcohol solvent to dissolve the diamine. The hydrogen cyanide utilized in the reaction is conveniently prepared in situ by reacting a cyanide salt with an acid. This is ordinarily accomplished by adding an aqueous solution of the cyanide salt to a mixture containing the 1,2-diaminobenzene compound, water or methanol, and aqueous hydrochloric acid. The quantities of reagents are preferably adjusted so that the pH of the resulting mixture is approximately 6.5-7 .0. If desired, a smaller quantity of hydrochloric acid may be used in the initial mixture and the resulting alkaline cyanide solution acidified to a pH of 6.5-7.0 by the subsequent addition of hydrochloric acid. Instead of using a cyanide salt plus hydrochloric acid, the proper amount of hydrogen cyanide can be added to a mixture of the diamine and water; or diamine, water and methanol, (or other lower aliphatic alcohol solvent) which automatically gives the proper pH. The reaction is preferably carried out by adding the formaldehyde to a mixture containing the other components, at the same time maintaining the temperature below about 45 C. The N-(o-aminophenyl)-glycine nitrile compound, thus produced crystallizes during the course of the reaction and is recovered from the resulting slurry by filtration and centrifugation.

When the previously enumerated 1,2-diaminobenzene compounds are treated according to one of the foregoing procedures, there are obtained the corresponding substituted N-(o-aminophenyD-glycine nitrile compounds having the formula:

NHCHzCN conducted under an inert atmosphere, such as nitrogen, but this is not essential. In fact, if desired, oxygen can be bubbled through the reaction mixture during the cyclization, thereby cyclizing the nitrile compound and, at the same time, oxidizing the intermediate a4-am crcuinoxaline compound produced by said cyclization operation. It is ordinarily preferred, however, to conduct the cyclization under non-oxidizing conditions and then to oxidize the oyclization product in a separate oxidation step.

We have discovered that methanol is an essential component of the cyclization solution. Surprisingly enough, we have found that other lower aliphatic alcohols, such as ethanol, isopropanol and butanol are unsatisfactory for car rying out the cyclization reaction. Although it is possible to carry out the cyclization in aqueous methanol, we have found that the addition of water in excess of about 1% lowers the yield. We therefore prefer to employ substantially anhydrous methanol as the solvent for this reaction.

The base employed should be approximately equivalent stoichiometrically to the N (o-aminophenyD-glycine nitrile. Amounts of base varying between 0.5 and 1.2 times the stoichiometric equivalent of the nitrile have given satisfactory results; cyclization employing molecular proportions of base below or above this range have resulted in decreased yield of the desired product.

It has been found that the cyclization reaction can be carried out at temperatures within'the range of about C. to 60 C. It is preferred, however, to conduct the cyclization at a temperature between about 25 C. and 55 C., at which temperatures excellent yields of cyclization product are obtained. The time required for the obtainment of maximum yield varies depending on the temperature and the proportion of solvent from at least hours for cyclizations conducted at 55 C. to about 72 hours for cyclizations at 25 C. Longer cyclization periods have little or no effect on the yield. The 2-amino-3,4-dihydroquinoxaline compound produced is conveniently isolated from the cyclization reaction mixture by evaporating most of the methanol and diluting the concentrate with water and cooling, whereupon said 2-amino-3,4-dihydroquinoxaline compound crystallizes and can be recovered by conventional means.

When the aforementioned substituted N-(oaminophenyD-glycine nitrile compounds are treated according to the above-disclosed cyclization procedures, there are obtained the corresponding substituted 2-amino-3,4-dihydroquinoxaline compounds of the formula:

wherein R1 and R2 are nuclear substituents of the class which consists of hydrogen, halo, alkyl v and alkoxy radicals.

the previously disclosed halogenated, alkylated and alkoxy substituted 2-amino-3,4-di-hydroquinoxalines are not affected by the oxidation treatment with the result that the product in each case is the corresponding halogenated, al-

, and alkoxy radicals.

The oxidizing agents ordinarily employed in this reaction include alkaline potassium ferricyanide, hydrogen peroxide under either acid or alkalinegconditions, palladium-activated charcoal, ferric chloride, air, oxygen; it is ordinarily preferred to use hydrogen peroxide. When hydrogen peroxide is used as the oxidizing agent, it is preferably employed in conjunction with materials which are known to catalyze the decomposition of hydrogen peroxide, such as ferrous chloride. A list of such decomposition catalysts is given on page 24 of the text Reference Book of Inorganic Chemistry by Latimer and Hildebrand-N. Y., 1937, MacMillan Co.

The reaction between the 2-amino-3,4-dihy droquinoxaline compound and alkaline potas-- sium ferricyanide is best carried out by heating the reactants in aqueous solution, preferably at a temperature of approximately 80-85 C. When alkaline hydrogen peroxide is used as the oxidizing agent, any temperature from about 0 C. to over C. can be employed. The reaction between the 2-amino-3,4-dihydroquinoxaline compound and hydrogen peroxide takes place spontaneously with evolution of heat and thereaction temperatureis ordinarily maintained within the preferred range by cooling the reaction mixture. If desired, however, "the reaction mixture can be heated at the start of the reaction, thereby shortening the total reaction time. The time ordinarily required for the oxidation varies depending on the concentration of oxidizing agent, temperature of-oxidation, etc., from about 30 minutes up to about 4 hours. The reaction solution is then cooled and the desired 2-amino-quinoxaline compound crystallizes directly therefrom and is recovered by filtration or centrifugation.

The reaction between the 2-amino-3,4-dihydroquinoxaline compound and palladium-activated charcoal is carried out by heating the reactants under reflux in tetralin solution. Under these conditions the reaction is substantially complete in approximately 1 hour. The catalyst is removed from the'reaction mixture, while still hot, by filtration or centrifugation, and the resulting tetralin solution is cooled to crystallize the desired z-aminoquinoxaline compound. This crude product is recovered by filtration, washed with petroleum ether, and may be further purifled by precipitation from its solution in aqueous mineral acid by the addition of an alkaline material.

When ferric chloride, hydrogen peroxide, or oxygen are employed as the oxidizing agent, the reaction is conveniently conducted by adding the oxidizing agent directly to the methanolic cyclization solution, thus avoiding the need for isolating the 2-amino-3,4-dihydroquinoxaline compound. Moreover, a simultaneous cyclization and oxidation can be accomplished therebyconverting the o-(aminophenyl) -glycine nitrile compound directly to the 2-aminoquinoxaline compound in a single operation.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not or limitation.

Example 1 A suspension of 108 g. of o-phenylenediamine in 200 cc. of water was treated with a freshly made solution of 114.4 g. of sodium bisulfite and 90 g. of 36% formaldehyde solution in 200 cc. of water. The mixture, which became slightly warm, was stirred for 2 hours, when solution became complete. After Standing overnight at room temperature this solution was warmed to 60 C. for 4 hours and then treated with a solution of 54 g. of sodium cyanide in 100 cc. of water. The mixture was held at 80-85 C. for minutes, then cooled to 20 C., filtered, and the filtered product washed with ice water. The wet product was substantially dissolved in 400 cc. of hot isopropanol, some insoluble material filtered off, and the filtrate chilled to 2 C. overnight. The crystals were collected, washed with cold isopropanol and dried to give 62 g. (42% of theory) of product; M. P.:103-l05 C. Recrystallization of this material from benzene gave pure N-(o-aminophenyi)-glycine nitrile as lustrous leaflets of M. P. 110.5-111 C.; Anal. Calcd for CaHoNa: C, 65.27; H, 6.16; H, 28.54. Found: C, 65.07; H, 6.31; H, 28.75.

Example 2 aminophenyll-glycine nitrile; M. P. 102-105" C.

A mixture of this product with material prepared as in Example 1 showed no depression in melting point.

Example. 3

To a solution of 27.0 g. of o-phenylenediamine in 120 cc. of 2.5 N hydrochloric acid and 55 cc. of methanol was added 14.7 g. of sodium cyanide. With the temperature at -45 C., 20.8 g. of 36-38% solution of formaldehyde in water was added over 15 minutes. Slight cooling was necessary to keep the temperature below 45 C. When about /2 of the formaldehyde was added, a crystalline precipitate of N-(o-aminophenyl)- glycine nitrile appeared. The slurry was stirred for an hour at room temperature and an hour at 0-5 C. before filtration. The residue was washed free of chloride with cold water, and recrystallized from 60 cc. of boiling isopropanol without being dried. After holding at 0-5" G. for 4-6 hours, the crystalline product was collected, washed with ice-cold isopropanol and dried. The weight of the N-(o-aminophenyl) -glycine nitrile was 30.6 g. or 83.1% of theory; M. P.:104-106 C. By the method of solubility analysis, this material was shown to be over 80% pure. The chief impurity was N,N-dicyanomethyl-o-phenylenediamine.

Example 4 250 cc. of water, 135.00 gms. (1.25 moles) of o-phenylenediamine and 145 /2 gms. of aqueous solution of glycolonitrile (1.25 moles) are mixed together and heated to about 30-35 C. The initial pH of this solution which is aboutfi is adjusted to 6.5-7.0 by the addition of 2.5 N

sodium hydroxide solution, aboutfi cc. being required. The resulting mixture (volume about 500 cc.) is then heated to til-65 C. and maintained at this temperature for approximately 2 hours. Mild heat evolution occurs for about 1 hour from the time the mixture reaches a temperature of approximately 60 C. The diamine dissolves at 50 C. and, after about 20 minutes at a temperature of 60-65 C., an oil separates which upon seeding becomes crystalline. After the 2 hour heating period, the reaction mixture is cooled to room temperature and maintained at this temperature for at least 2 hours. The reaction mixture is then filtered and the crystalline product washed with three 100 cc. portions of water and dried at 45-50 C. to produce 151-1565 gms. of sandy, light brown N-(o-aminophenyhglycine nitrile; M. P. 101-105 C.; yield approximately 82-85% of theory.

Example 5 Example 6 o-Phenylenediamine was reacted with glycolonitrile substantially as described in Example 4,

except that 10% excess of glycolonitrile was employed. The quantity of N-(o-aminophenylglycine nitrile obtained was approximately 93% of that theoretically obtainable; M. P. -95 C.

Example 7 o-Phenylenediamine and glycolonitrile were reacted together substantially as described in Example 4, except that only 94% of the theoretical quantity of the glycolonitrile was employed. The quantity of N-(o-aminophenyl) -glycine nitrile thus obtained was 82.2% of theory; M. P. 102- 105 C.

Example 8 Exampl 9 o-Phenylenediamine was reacted with glycolonitrile substantially as described in Example 4 except that, only 94% of the theoretical equivalent of glycolonitrile was employed. As a result of the phosphoric acid added by the manufacturer to stabilize the glycolonitrile, the pH of the starting mixture thus prepared was about 6.0-6.2. Under these slightly acid conditions, no reaction occurred until the temperature reached C. After /3 hour at 90 C. the reaction mixture was treated as described in Example 4 to produce N-(o-aminophenyl) -glycine nitrile in a yield of approximately 88.7% of theory; M. P. 88-89 C.

Example 10 Condensation between glycolonitrile and ophenylenediamine was carried out substantially as described in Example 4 except that the reac- Example 11 stantially pure material; M. P. 104-105 C.

Example 12 Equimolecular amounts (1% moles) of o-phenylenediamine and technical glycolonitrile (50% aqueous solution) were heated together, without additional diluent, at 90-95 C. for a period of approximately hour. 75 cc. of isopropanol was product, which separated, recovered by filtration and dried to produc a yield of N-(o-aminophenyD-glycine nitrile in a yield of approximately 74.5% of theory; M. P. 99-102 0.

This reaction was carried out as described above, except that the reaction mixture was heated at 90-95 C. for 1 hour. The yield and quality of the product was identical with that obtained in the foregoing experiment.

Example 13 135.0 gms. of o-phenylenediamine, 142.5 gms. of 50% aqueous solution of glycolonitrile and 250 cc. of water were mixed together and the pH of the mixture adjusted to about 6.5-7.0. Th resulting mixture was then heated at a temperature of 90-95 for a period of 1 hour, 50 cc. of isopropanol was added to the hot mixture and the resulting mixture was cooled to -5 C. The crystalline product which separated was recovered by filtration and dried at 45--50 C. to produce crude N-(o-aminophenyl)-g1ycine nitrile in a yield of approximately 78% of theory; M. P. 92-98 C.

Example 14 mole of o-phenylenediamine and A mole of glycolonitrile (50% aqueous solution) were mixed with 55 cc. of methanol in 127 cc. of water and the pH of th mixture was adjusted to 6.5-7.0. The resulting mixture was heated at 60-65 C. for approximately 1 hour. The reaction mixture was cooled to 0 0.; the crystalline product which separated was recovered by filtration and dried to produce crude N-(o-aminophenyl) -glycine nitrile in a yield of 77% of theory; M. P. 88-100 C.

Example 15 One quarter mole of o-phenylenediamine was dissolved in a mixture containing 24 cc. of methanol and 24 cc. of water and the pH of the solution was adjusted to 6.5-7.0. The resulting solution was heated to 75-80 C. and A mole of glycolonitrile was added to the resulting solution over a period of 40 minutes While maintaining the temperature of the resulting mixture at 75-80 C.

and dried to produce a crystalline product; M. P. below 75 0.; assuming the product fr) he N-(oaminophenyD-glycine nitrile, the yield was approximately 63% of theory.

Exampl 16 methanol and the mixture agitated until solution was essentially complete. After standing at room temperatur for 48 hours a small amount of insoluble material was removed and the filtrate concentrated dry in vacuo. The residue was slurried with 50 cc. of water (at 50 C.) cooled to 2 C. overnight, filtered, washed with ice water and dried. The weight of product obtained was 32.5 g.; M. P. 151 C.; yield 63.1% of theory.

Recrystallization from benzene-petroleum ether gave pale yellow needles of 2-amino3,4-dihydroquinoxaline; M. P. 151 C.; Anal, Calcd for CaHsNa: C, 65.27; H, 6.16; N, 28.54, Found C, 65.12; H, 6.08; N, 28.63.

Example 1 7 Example 1 8 A mixture of 0.5 g. of 2-amino-3,4-dihydroquinoxaline. 0.05 g. of 10% palladium on Norit (an activated charcoal product) and 7 cc. of

tetralin was refluxed for one hour. After filtration from the catalyst, the filtrate was cooled arated, melted at 154-l56 C. and a mixture with authentic 2-aminoquinoxaline melted at the same temperature.

Example 1.9

14.7 g of 2-amino-3,4-dihydroquinoxa1ine was dissolved in a hot solution containing 5 g. of sodium hydroxide in 150 cc. of water, and 21 cc. of 30% hydrogen peroxide was added portion-wise to this solution; over 15 minutes at -85 C. The resulting solution was maintained at 80 C. for five minutes longer, then cooled to 21.4 g. of 2-amino-3,4-dihydroquinoxaline was dissolved in 400 cc. of warm water, and a hot solution of 99 g. of potassium ferricyanidein 250 cc. of 10% sodium hydroxide added-the temperature of the mixture was 70 C. Crystallization beganat once, and after standing for hour, the mixture was cooled to 5 C. and filtered. The crystals were washed with ice water and a few hours.

dried, to produce 13.0 g. of 2-aminoquinoxaline; M. P. 151.5-153.5 0.; yield 61% of theory.

Example 21 A suspension of N-(o-aminophenyl)-glycine nitrile (7.4 g., 0.05 mole) in 65 cc. of methanol I was treated with a solution of 3.1 g. (0.0755 mole) Example 22 Cyclization was carried out as described in Example 21 and the resulting solution was treated directly, without concentrating, with 0.1 g. finely ground FeCl24I-I2O and a hydrogen peroxide solution prepared by diluting 5.2 cc. of 30% hydrogen peroxide to 17 cc. with water. The methanol solution containing the iron catalyst was stirred and held at 2530 C. while the hydrogen peroxide was added portionwise over a 2 hour period. 0.5 g. of activated charcoal (Norit) was added and the mixture was filtered. The filtrate was concentrated to a volume of 50 00., 50 cc. of water added and the mixture again concentrated to a volume of 50 cc. The slurry wasrefrigerated overnight and then filtered, washed and dried. A direct yield of 4.5 g. (61.7% of theory) was ob' tained. This material formed pale cream-colored needles which melted at 154.5-155.8 C. A slightly less pure second crop raised the yield to 70% of theory.

Example 23 A suspension of 7.4 g. (0.05 mole) of N-(oamino-phenyl)-glycine nitrile in 65 cc. of methanol was stirred and treated with a solution ofv 3.1 g. (0.055 mole) of KOl-I in 50 cc. of methanol (nitrogen atmosphere). The clear solution which soon resulted was allowed to stand at room temperature for 20 hours, then concentrated to dry ness under a nitrogen atmosphere and under reduced pressure. The residue was slurried with 30 cc. of water and the slurry cooled to C. for

The solid was collected by filtration, washed with ice water and dried in vacuo. Weight:5.5 g. or 74.3% of theory; M. P.:140- 142 C. This material crystallized from ethyl acetate in hard prisms typical of 2-amino-3,4- dihydroquinoxaline.

Example 24 N-(o-aminophenyl) -glycine nitrile was treated as described in Example 23, but with the addition of 17 cc. of water (15% methanol volume). After standing 24 hours at room temperature a small sample was worked up to give 2-amino-3,4- dihydroquinoxaline; M. P.:138-142 C. The rest of thesolution was oxidized as described in Example 22. A 43.8% yield of 2-aminoquinoxaline (M. P.:155-156 C.) was obtained.- This yield is about 20% lower than is obtained under anhydrous conditions.

Example 25 A suspension of 6.6 g. (0.045 mole) of N-(oamino-phenyl)-glycine nitrile in 56 cc. of methanol was treated with a mixture of 22 g. of 38% aqueous solution of trimethylbenzylammonium hydroxide (0.05 mole) and 45 cc. of methanol and the mixture was allowed to stand at room temperature for 24 hours. One half of the resulting solution was oxidized as described in Example 22 using 0.03 finely ground FeClzAHaO and 2.3 cc. of 30% hydrogen peroxide (Super- 0x01) diluted to 7 cc. with water. After concentration to small volume and dilution with water, nicely crystalline 2-aminoquinoxaline separated. The weight was 1.8 g. or 55% of theory; M. P.:153-155 C.

Example 26 aminophenyl)-glycine nitrile in 56 cc. of methanol. After 24 hours at room temperature under a nitrogen atmosphere, the resulting solution was divided in halves and one of these oxidized as described in Example 22. The yield of 2-aminoquinoxaline was 2.0 g. (61.2% of theory) M. P.:155-156 C.

Example 27 A suspension of 66.3 g. (0.45 mole) of N-(oaminophenyl) -glycine nitrile in 563 cc. of methanol was stirred at room temperature, nitrogen was bubbled thru the mixture and a cold solution of 27.9 g. (0.497 mole) of potassium hydroxide in 450 cc. of methanol was added. The temperature remained unchanged and after about 10 minutes a clear solution resulted. The nitrogen stream and stirring was then discontinued and the resulting solution was allowed to stand in a closed flask at room temperature for 24 to 30 hours.

0.6 g. of finely ground FeChAHzO was added to the cyclization solution. 46.5 cc. of Superoxol (which contained 15.35 g. of hydrogen peroxide) was diluted to cc. with water and this solution was added in 15 cc. portions to the cyclization solution. The mixture was stirred and the temperature held between 25 and 30 C. by slight cooling. Between additions, the reaction mixture was stirred until the hydrogen peroxide was entirely consumed. After the addition was complete, the reaction mixture was stirred until a negative peroxide test was obtained; the total time required for the oxidation was approximately 2 to 3 hours.

3 g. of activated charcoal (Norit) was added to the reaction mixture and the mixture was stirred for 15 minutes. The mixture was then filtered and the charcoal cake was washed with 50 cc. of methanol. The filtrate and washings were combined and concentrated under reduced pressure at a temperature of 40 C. until the volume was 500-600 cc. 300 cc. of water was added and the distillation continued until the volume was again 600 cc. Crystallization occurred toward the end of the concentration and the slurry became so thick as to impede concentration if the inside temperature was allowed to fall below 40 C. The slurry was cooled to 0-5 C. for at least two hours before filtering. The product was washed free of hydroxyl ion with about 250 cc. of ice water and dried at 65 C. to produce 42.5 to 44.5 g. of ivory-colored matted needles of 2-aminoquinoxaline; M. P, 154.5-156 C.; yield 65-68% of theory.

' Example 28 Example 29 0.6 g. of finelyground FeClz.4HzO was addedto a cyclization solution prepared from 66.3 g. of N -(o-aminophenyl)-glycine nitrile as described in either Example 27 or 28. The resulting mixture was stirred at -5 C. (the low temperature minimizes loss of methanol and danger of an explosive air-methanol mixture) and dry carbon dioxide-free air was passed in slowly for 15 to 24 hours. 3 g. of activated charcoal (Norit) was added and the mixture worked up as described in Example 27 to produce about 45 g. of Z-aminoquinoxaline. Yield approximately 68% of theory.

Example 30 A cyclization solution prepared as described in Example 28 from 17.1 g. (0.116 mole) of N-(o aminophenyD-glycine nitrile in 145 cc. methanol plus 2.9 g. (0.126 atom) sodium in 116 cc. of methanol, was treated with 2.5 N HCl until the solution was no longer alkaline to phenolphthalein (ca. 53 cc. required). 68.5 g. of ferric chloride hexahydrate was added and the mixture let stand for 15 minutes (temperature rose a few degrees). 5.0 g. of filter cel (Supercel) and then 30% sodium hydroxide were added until the mixture was alkaline to phenolpthalein (ca. 82 cc. required). The slurry of ferrous hydroxide was heated to 75 C. and filtered thru filter cel (Supercel). The residue was washed with 50 cc. of hot methanol. The filtrates were combined and concentrated until quite thick with precipitated 2-aminoquinoxaline. The slurry was cooled to 0-5 C. for one hour. filtered and the filter cake washed free of sodium hydroxide and dried. The weight of 2-aminoquinoxaline was 2.8 g. (46.5% of theory); M. P.=148-150 0.

Example 31 1.47 g. (.01 mole) of 2-amino-3,4-dihydroquinoxaline was dissolved in 6 cc. ofwater plus 4 cc. of 2.5 N HCl. 2.00 cc. of 30% aqueous hydrogen peroxide (Superoxol) was added and the mixture held at room temperature for 10 minutes. 8 cc. additional 2.5 N H01 was added to the solution and the solution was then warmed to 80 C. for 2-3 minutes. The reaction solution was cooled and made alkaline with 4-5 cc. of 30% sodium hydroxide solution. The precipitated material was recovered by filtration, washed with water and dried. The weight of Z-aminoquinoxaline was 1.2 g. (82.0% of theory), M. R: 149-152 C. A mixed M. P. with authentic 2- aminoquinoxaline was not depressed.

Example 32 -glycine nitrile L cc. of water was added and nitrile in a dry carbon dioxide free air; After 48 hours 50 ture was concentrated to a volume of about 50 cc. The slurry was refrigerated overnight and then filtered, washed and dried. The yield ot 2-aminoquinoxaline or M. P.=149-154 C. was 3.7 g. or 51% of theory. 4

Example 33 A cyclization solution, prepared as described in Example 27, from 1.47 g. (.01 mole) of N-(oaminophenyD-glycine nitrile in 12.5 cc. methanol plus 0.25 g. sodium in 10 cc. of methanol, was

4-methyl-1.2-diaminoben2ene. formaldehyde and hydrogen cyanide were reacted together acsponding N 2 amino methylphenyl) glycine yield of approximately 86.3% of theory.

16.1 gms. of this nitrile was addedto a solution containing 6.2 gms. of potassium hydroxide dissolved in 135 cc. of methanol,

amino methyl 3,4 dihydroquinoxaline. compound can be isolated, if desired by evaporat- 0.13 gm. of finely ground ferrous chloride however, added to the methto destroy excess hydrogen peroxide. The solution was treated with activated charcoal, filtered and evaporated to a, volume of approximately duce about 9.5 gins. methylquinoxaline;

This product was purified by recrystallization from benzene to produce substantially pure material; M. P. 174-1755 and hydrogen cyanide were reacted together acthe reaction mix-- 15 cording to substantially the same procedure employed in the case of o-phenylenediamine and described in Example 3. The crystalline product thus obtained was dried to produce the corresponding N-(2-amino-methylphenyl) -glycine nitrile in a yield of approximately 61% of theory;

-M. P. I l-84 C 24.75 gms. of this nitrile was dissolved in 92 cc. of methanol containing 36 gms. of potassium hydroxide and the solution was allowed to stand at room temperature under nitrogen for about 72 hours. The dihydroquinoxaline present in this solution is isolated by evaporating the nitrile under reduced pressure, trituratin the residual material with water, filtering the crystalline slurry thus obtained, and drying to produce the corresponding 2 amino methyl 3,4 dihydroquinoxaline.

Instead of isolating the dihydroquinoxaline, however. the methanolic reaction solution obtained above was oxidized as follows: 0.2 gm. of ferrous chloride tetrahydrate was added to the reaction solution, and a solution of 15.8 cc. of Superoxol (diluted to 51 cc. with water) was then added to this reaction solution over a period of 1 hour while the temperature was maintained at approximately 30 C. The reaction mixture was then stirred for an additional 1 hour period and a trace of sodium sulfite was added thereto to destroy excess hydrogen peroxide. The solution was treated with activated charcoal, filtered and evaporated to a volume of approximately 150 cc. About 75 cc. of water was then added to this solution and the resulting solution again concentrated to about 150 cc. whereupon a crystalline product separated. This product was recovered by filtration, washed and dried to produce a 51% 'yield of the corresponding 2-amino-methylquinoxaline; M. P. 129131 C. This product was purified by recrystallization from benzene to produce substantially pure 2-amino-methylquinoxaline monohydrate; M. P. 135-136 C. Anal. Calcd fOl C9H11N3O: C, 61.10; H, 6.26; N, 23.70; Found: C, 61.33; H, 5.95; N, 23.30. After drying at 100 C. at 1-2 mm. pressure, anhydrous material of the same M. P. was obtained. Anal. Calcd for CeHsNsZ C, 67.90; H, 5.70; Found: C, 68.01; H, 5.79.

According to this process only one isomer (either the 5 or 8 methyl derivative) was obtained. From stereochemical considerations it appears likely that the particular isomer obtained according to the foregoing procedure was 2-amino-8- methylquinox-aline. The corresponding precursors would therefore be 2-amino-8-methyl-3,4- dihydroquinoxaline and N-(2-amino-3-methylphenyl)-glycine nitrile (M. P. 74-84 0.). The other isomer, which has been prepared by a modified procedure, melts at 202-203 C. and appears to be 2-amino-5-methyl-quinoxaline.

Example 36 3.56 gms. (0.25 mole) of 4-ch1oro-1,2-diaminobenzene were heated with 2.85 gms. (0.25 mole) of 50% aqueous glycolonitrile solution for a period of 1 hour at a temperature of approximately 100 C. 7.5 cc. of isopropanol was added to the hot reaction solution, activated charcoal was added to the resulting mixture which was filtered hot and the filtrate cooled in ice. The crystalline product which separated was recovered by filtration and dried to produce a mixture of N-(2- amino-4-chlorophenyl) -glycine nitrile and N-(2- amino 5 chlorophenyl) glycine nitrile; M. P.

81.5-85.5 0.; yield approximately 31% of theory. 2.6 gms. of this nitrile was mixed with 0.9 gm.

of potassium hydroxide and 23 cc. of methanol and the resulting solution allowed to stand under nitrogen for 3 days.

The resulting solution is evaporated to dryness under reduced pressure, the residual material triturated with water and the crystalline product.

filtered and dried to produce a mixture of 2-amino-6-chloro-3,4-d1hydroquinoxaline and 2- -amino-7-chloro-3.4-dihydroquinoxaline.

Alternatively 0.2 gm. of finely ground ferrous chloride tetrahydrate was added to the reaction solution followed by a solution containing 1.5 cc. of Superoxol diluted to 5 cc. with water. After the resulting solution had been allowed to stand for 15 minutesycrystals began to separate and after 45 minutes all of the peroxide had been consumed. Two different isomeric products were obtained by fractional crystallization of this reaction mixture: the first (27% of theory) melted at 215-216 C. and after purification by recrystallization from alcohol yielded needles melting at 21'7-219 C. The second crop (22 of theory) recovered from this liquor melted at 185190 C.

Analysis of the isomer melting at 215-216 C.; Calc'd for'CaHsNsCl: C, 53.49; H, 3.73; Found:

53.22; H, 3.50; one of the above isomers is Example 37 4-methoxy-1,2-diaminobenzene, formaldehyde and hydrogen cyanide were reacted together according to substantially the same procedure employed in the case of o-phenylenediamine and described in Example 3. The crude material obtained according to this procedure was gum from which the corresponding N-(2-aminomethoxyphenyD-glycine nitrile was obtained as a semisolid in about 50% yield after digestion with chloroform and benzene mixtures.

A solution containing about 17.7 gms. of this nitrile and 6.2 gms. of potassium hydroxide in 210 cc. of methanol was allowed to stand at room temperature under nitrogen for 3 days.

This solution is evaporated under reduced pressure, the residual material is triturated with water and the crystalline product thus obtained recovered by filtration and dried to produce the corresponding crude 2 -amino-methoxy-3,4-dihydroquinoxaline.

Instead of isolating the dihydroquinoxaline compound, however, 0.13 gm. of finely ground ferrous chloride tetrahydrate was added to the methanolic. reaction solution without further treatment thereof, and a solution containing 10.3 cc. of Superoxol diluted to 33 cc. with water was then added to this reaction solution over a period of 1 hour while maintaining the reaction temperature at approximately 30 C. The reaction mixture was then stirred for an additional 1 hour period and a trace of sodium sulfite was added thereto to destroy excess hydrogen peroxide. The solution was treated with activated charcoal, filtered and evaporated to a volume of approximately cc. About 65 cc. of water was then added to this concentrated solution and the resulting soltuion again concentrated to 100 cc. whereupon a crystalline product separated. This product was recovered by filtration, washed and dried to produce the corresponding 2-amino-methoxy-quinoxaline; M. P. 200-205 0.; yield approximately 72% of theory. This product was purified by repeated precipitation from low feathery needles; M. P. 216.5-217.5 C. Anal.

Calcd for CaHcONs: C. 61.70; H, 5.20; Found: C, 61.99; H, 5.21. a V

.E'xample 38 f 66.3 g. of purified N-(o-aminophenyl)-glycine nitrile, having a M. P. of 110-111" C. and a purity of about 95% by solubility analysis, was dissolved in 600 cc. of methanol containing 13.5 g. of potassium hydroxide and the solution was maintained at 35-40" C. for 17 hours under a nitrogen atmosphere. The resulting mixture was oxidized using hydrogen peroxide and ferrous chloride in the usual manner, thereby producing 2-aminoquinoxaline (M. P.=156-157.5 c.) which was isolated in a yield of 85% of theory. r Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changesand modifications are within the scope of the annexed claims, they are to be considered as part of our invention.

We claim: x

1. The process of preparing z-amino-quinoxaline compounds which comprises reacting an c-substituted acetonitrile compound, selected from the group which consists of glycolonitrile, haloacetonitriles and the product of the reaction between formaldehyde and hydrogen cyanide, with a 1,2-diaminobenzene compound having the formula:

wherein R and R2 have the significance above defined, and reacting said 2-amino-3,4-dihydroquinoxaline compound with an oxidizing agent' selected from the group consisting of alkaline potassium ferricyanide, hydrogen peroxide, ferric chloride, air, and oxygen.

2. The process ofpreparing 2-aminoquinoxaline which comprises reacting o-phenylenediamine with formaldehyde and hydrogen cyanide to produce N-(o-aminophenyl) -g1ycine nitrile, treatingthis compound with a methanolic solution of a strong base to form 2-amino-3,4dihydroquinoxalme, and reacting said 2-amino-3,4- dihydroquinoxaline with an oxidizing agent selected from the group consisting of alkaline potassium ferricyanide, hydrogen peroxide, ferric chloride, air, and oxygen.

3. The process of preparing Z-aminoquinoxaline which comprises reacting o-phenylenediamine with formaldehyde and hydrogen cyanide, said reaction being carried out in aqueous methanol, to produce N-(o-aminophenyl)-glycine nitrile, treating this compound with a substantially anhydrous methanolic solution of potassiumhydroxide, and adding ferrous chloride and hydrogen peroxide to the resulting solution.

4. The process or preparing 2-amino-6-chloroquinoxaline which comprises reacting 4-chloro- 1,2-diaminobenzene with glycolonitrile to produce N-,(2-amino-5-chlorophenyl) -g1ycine .nitrile, treating this compound with a methanolic solution of potassium hydroxide thereby forming 2 amino e 6 chloro-3.4-dihydroquinoxaline, and reacting the latter compound with hydrogen peroxide in a medium comprising aqueous methano I 5. The process of preparing z-aminoquinoxaline which comprises reacting N-(o-aminophenyD-glycine nitrile with a substantially anhydrous methanolic solution of potassium hydroxide, and adding hydrogen peroxide and fer-i rous chloride to the resulting solution.

6. The process of preparing Z-aminoquinoxaline which comprises reacting 2-amino-3,4-dihydroquinoxaline with an oxidizing agent selected from the group consisting of alkaline potassium ferricyanlde, hydrogen peroxide, ferric chloride, air, and oxygen.

7. The process of preparing 2-aminoquinoxaline which comprises reacting -2-amin0-3,4-dihydroquinoxaline with hydrogen peroxide.

8. The process of preparing 2-:aminoquinoxaline which comprises adding hydrogen peroxide and ferrous chloride to a substantially anhydrous methanolic solution containing potassium hydroxide and 2-amino-3,4-dihydroquinoxaline, and heating the mixt re thus obtained.

9. The process of preparing z-amino-methylquinoxaline monohydrate having a melting point of approximately 136 C., and the probable formula:

which comprises reacting the corresponding 2-amino-methyl-3,4-dihydroquinoxaline with hydrogen peroxide, said reaction being carried out in a medium comprising aqueous methanol.

10. The process chloroquinoxaline which comprises reacting 2 amino-6-chloro-3,4-dihydroquinoxaline with hydrogen peroxide, said reaction being carried out in a medium comprising aqueous methanol.

11. The process of preparing the Z-aminomethoxy-quinoxaline having a melting point of approximately 217.5 C. and the probable formula:

12. The process of preparing 2-amino-7-chloro- I quinoxaline which comprises reacting 2-aminoof preparing z-amino-fi 19 'I-chloro-3-,4-dihydroquinoxaline with hydrogen peroxide, said reaction being carried out in a medium comprising aqueous methanol.

13. The process of preparing 2-aminoquinoxaline compounds which comprises reacting the corresponding N-(o-aminophenyl) -g1ycine nitrile 20 ing of alkaline potassium terricyanide,- hydrogen peroxide, ferric chloride, air, and oxygen with the corresponding 2-amino-3,4-dihydroquinoxaline compound.

KARL PFIS'I'ER III. JOHN WEIJLARD.

. References Cited in the file of this patent Beiistein, Vierte Auflage. vol. 13. p. 105. 

1. THE PROCESS OF PREPARING 2-AMINO-QUINOXALINE COMPOUNDS WHICH COMPRISES REACTING AN A-SUBSTUTUTED ACETONITRILE COMPOUND, SELECTED FROM THE GROUP WHICH CONSISTS OF GLYCOLONITRILE, HALOACETONTRILES AND THE PRODUCT OF THE REACTION BETWEEN FORMALDEHYDE AND HYDROGEN CYANIDE, WITH A 1,2-DIAMINOBENZENE COMPOUND HAVING THE FORMULA: 